CA2985271A1 - A method for treating diabetes - Google Patents
A method for treating diabetesInfo
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- CA2985271A1 CA2985271A1 CA2985271A CA2985271A CA2985271A1 CA 2985271 A1 CA2985271 A1 CA 2985271A1 CA 2985271 A CA2985271 A CA 2985271A CA 2985271 A CA2985271 A CA 2985271A CA 2985271 A1 CA2985271 A1 CA 2985271A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
- C07J41/0011—Unsubstituted amino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
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- Obesity (AREA)
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- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
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Abstract
This application is directed to the use of steroid compounds for the selective inhibition of the enzyme PTP1B in a mammal for the treatment of diabetes.
Description
A Method for Treating Diabetes CROSS REFERENCE TO RELATED APPLICATIONS
10001.1 This application claims priority to U.S. Provisional Application No.
60/970,467, filed Sept. 6, 2007 FIELD OF THE INVENTION
100021 This application is directed to the use of steroid compounds for the selective inhibition of the enzyme PTP1B in a manunal for the treatment of diabetes.
BACKGROUND OF THE INVENTION
[00031 Several aminosterol compounds have been isolated from the liver of the dogfish shark, Squall's acanthias. One of these compounds has been designated as 1436, the structure of which is shown in FIG. 1. Compound 1436 has been previously described in, e.g., U.S. Patent Nos. 5,763,430; 5,795,885; 5,847,172; 5,840,936 and 6,143,738, and has been shown to inhibit weight gain and suppress appetite, which leads to weight loss in animal models.
100041 Diabetes is a major medical problem in the United States and increasingly so in the rest of the developed world. Type II diabetes in particular is caused primarily by the effects of a sedentary life style and a fat-rich diet The diabetic individual is susceptible to medical problems directly related to his disease such as elevated serum cholesterol, high blood pressure, congenital obesity syndromes (including congenital leptin, pro-opiomelanocortin (POMC) and melarrocortin-4 receptor (MC4R) deficiencies), and sleep apnea, especially in pickvvickian syndrome. In addition, the accumulation of fat in the liver can progress to nonalcoholic steatohepatitis and cirrhosis. Another problem for obese diabetic individuals is an increased risk in any surgery that must cut through thick layers of fatty tissue that are highly vascularized and therefore prone to hemorrhage.
Necessary surgery is frequently postponed until this diabetic patient can lose sufficient weight to make the risk of the operation acceptable.
100051 Insulin is an important regulator of different metabolic processes and plays a key role in the control of blood glucose. Defects related to insulin synthesis and signaling lead to diabetes mellitus. Binding of insulin to the insulin receptor (IR) causes rapid autophosphorylation of several tyrosine residues in the intracellular part of the beta-subunit Three closely positioned tyrosine residues (the tyrosine-1150 domain) must be phosphorylated to obtain maximum activity of the insulin receptor tyrosine kinase (1RTK), which transmits further signals via tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2).
100061 Protein phosphorylation is a well-recognized cellular mechanism for transducing and regulating signals during different stages of cellular function (see, e.g., Hunter, Phil, Trans. R. Soc. Lond. B. 353: 583-605 (1998); Chan et al., Armu. Rev. Immunol.
12: 555-592 (1994); Zhang, Carr. Top. Cell. Reg. 35: 21-68 (1997); Matozald and Kasuga, Cell.
Signal. 8: 113-119 (1996)). There are at least two major recognized classes of phosphatases: (1) those that dephosphorylate proteins that contain a phosphate group(s) on a serine or threonine moiety (termed SerfTbr phosphatases or dual specificity phosphatases or DSPs) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs).
[00071 Several studies clearly indicate that the activity of the auto-phosphorylated IRTK
can be reversed by dephosphorylation in vitro (reviewed in Goldstein, Receptor 3: 1-15 (1993)) with the tri-phosphorylated tyrosine-1150 domain being the most sensitive target for PTPases. 'This tri-phosphorylated tyrosine-1150 domain appears to function as a control switch of IRTK activity and the IRTK appears to be tightly regulated by PTP-mediated dephosphorylation in vivo (Faure et aL, J. Biol. Chem. 267: 11215-(1992)).
[00081 PTP1B has been identified as at least one of the major phosphatases involved in ERTK regulation through studies conducted both in vitro (Seely et al., Diabetes 45: 1379-1385 (1996)) and in vivo using PTP1B neutralizing antibodies (Alunad et al., J. Biol.
Chem. 270: 20503-20508 (1995)). Three independent studies have indicated that knock-out mice have increased glucose tolerance, increased insulin sensitivity and decreased weight gain when on a high fat diet (Elchebly et al., Science 283:
(1999), Kiernan et al., Mol. Cell. Biol. 20: 5479-5489 (2000), and Bence et al., Nature Med (2006)). Overexpression or altered activity of tyrosine phosphatase PTP IB
can contribute to the progression of various disorders, including insulin resistance and diabetes (Ann. Rev. Biochem. 54: 897-930 (1985)). Furthermore, there is evidence which suggests that inhibition of protein tyrosine phosphatase PTP1B is therapeutically beneficial for the treatment of disorders such as type I and II diabetes, obesity, autoimmune disorders, acute and chronic inflammation, osteoporosis and various forms of cancer (Zhang Z Y et al., Expert Opin. Investig. Drugs 2: 223-33 (2003);
Taylor S D
10001.1 This application claims priority to U.S. Provisional Application No.
60/970,467, filed Sept. 6, 2007 FIELD OF THE INVENTION
100021 This application is directed to the use of steroid compounds for the selective inhibition of the enzyme PTP1B in a manunal for the treatment of diabetes.
BACKGROUND OF THE INVENTION
[00031 Several aminosterol compounds have been isolated from the liver of the dogfish shark, Squall's acanthias. One of these compounds has been designated as 1436, the structure of which is shown in FIG. 1. Compound 1436 has been previously described in, e.g., U.S. Patent Nos. 5,763,430; 5,795,885; 5,847,172; 5,840,936 and 6,143,738, and has been shown to inhibit weight gain and suppress appetite, which leads to weight loss in animal models.
100041 Diabetes is a major medical problem in the United States and increasingly so in the rest of the developed world. Type II diabetes in particular is caused primarily by the effects of a sedentary life style and a fat-rich diet The diabetic individual is susceptible to medical problems directly related to his disease such as elevated serum cholesterol, high blood pressure, congenital obesity syndromes (including congenital leptin, pro-opiomelanocortin (POMC) and melarrocortin-4 receptor (MC4R) deficiencies), and sleep apnea, especially in pickvvickian syndrome. In addition, the accumulation of fat in the liver can progress to nonalcoholic steatohepatitis and cirrhosis. Another problem for obese diabetic individuals is an increased risk in any surgery that must cut through thick layers of fatty tissue that are highly vascularized and therefore prone to hemorrhage.
Necessary surgery is frequently postponed until this diabetic patient can lose sufficient weight to make the risk of the operation acceptable.
100051 Insulin is an important regulator of different metabolic processes and plays a key role in the control of blood glucose. Defects related to insulin synthesis and signaling lead to diabetes mellitus. Binding of insulin to the insulin receptor (IR) causes rapid autophosphorylation of several tyrosine residues in the intracellular part of the beta-subunit Three closely positioned tyrosine residues (the tyrosine-1150 domain) must be phosphorylated to obtain maximum activity of the insulin receptor tyrosine kinase (1RTK), which transmits further signals via tyrosine phosphorylation of other cellular substrates, including insulin receptor substrate-1 (IRS-1) and insulin receptor substrate-2 (IRS-2).
100061 Protein phosphorylation is a well-recognized cellular mechanism for transducing and regulating signals during different stages of cellular function (see, e.g., Hunter, Phil, Trans. R. Soc. Lond. B. 353: 583-605 (1998); Chan et al., Armu. Rev. Immunol.
12: 555-592 (1994); Zhang, Carr. Top. Cell. Reg. 35: 21-68 (1997); Matozald and Kasuga, Cell.
Signal. 8: 113-119 (1996)). There are at least two major recognized classes of phosphatases: (1) those that dephosphorylate proteins that contain a phosphate group(s) on a serine or threonine moiety (termed SerfTbr phosphatases or dual specificity phosphatases or DSPs) and (2) those that remove a phosphate group(s) from the amino acid tyrosine (termed protein tyrosine phosphatases or PTPases or PTPs).
[00071 Several studies clearly indicate that the activity of the auto-phosphorylated IRTK
can be reversed by dephosphorylation in vitro (reviewed in Goldstein, Receptor 3: 1-15 (1993)) with the tri-phosphorylated tyrosine-1150 domain being the most sensitive target for PTPases. 'This tri-phosphorylated tyrosine-1150 domain appears to function as a control switch of IRTK activity and the IRTK appears to be tightly regulated by PTP-mediated dephosphorylation in vivo (Faure et aL, J. Biol. Chem. 267: 11215-(1992)).
[00081 PTP1B has been identified as at least one of the major phosphatases involved in ERTK regulation through studies conducted both in vitro (Seely et al., Diabetes 45: 1379-1385 (1996)) and in vivo using PTP1B neutralizing antibodies (Alunad et al., J. Biol.
Chem. 270: 20503-20508 (1995)). Three independent studies have indicated that knock-out mice have increased glucose tolerance, increased insulin sensitivity and decreased weight gain when on a high fat diet (Elchebly et al., Science 283:
(1999), Kiernan et al., Mol. Cell. Biol. 20: 5479-5489 (2000), and Bence et al., Nature Med (2006)). Overexpression or altered activity of tyrosine phosphatase PTP IB
can contribute to the progression of various disorders, including insulin resistance and diabetes (Ann. Rev. Biochem. 54: 897-930 (1985)). Furthermore, there is evidence which suggests that inhibition of protein tyrosine phosphatase PTP1B is therapeutically beneficial for the treatment of disorders such as type I and II diabetes, obesity, autoimmune disorders, acute and chronic inflammation, osteoporosis and various forms of cancer (Zhang Z Y et al., Expert Opin. Investig. Drugs 2: 223-33 (2003);
Taylor S D
2 et al., Expert Opin. Investig. Drugs 3:199-214 (2004); I. Natl. Cancer Inst.
86: 372-378 (1994); Mol. Cell. Biol. 14: 6674-6682 (1994); The EMBO J. 12: 1937-1946 (1993); J.
Biol. Chem. 269: 30659-30667 (1994); and Biochemical Pharmacology 54: 703-711(1997)). Agents that inhibit phosphatase activity and thereby inhibit dephosphoryiation of the insulin signaling pathway, increase whole-body insulin sensitivity. This is therapeutically beneficial in treatment of insulin resistance associated with Type 11 diabetes and obesity.
RON In addition, it has been shown (Bence ICK et al., Nat Med 8:917-24 (2006)) that neuronal PTP1B in the brain regulates body weight, adiposity and leptin action.
Therefore, if a PTP1B inhibitor can cross the blood brain barrier it will not only sensitize the effect of insulin but also result in weight loss an added benefit in the treatment of type Il diabetes and in addition the treatment of obesity and its complications.
10010] There is also reported insulin resistance in Type I diabetes for which agents with PTP1B inhibitory activity would be a useful therapeutic. An insulin sensitizing agent in early type I diabetes or in a pre-diabetic statue might delay the onset of diabetes by increasing the sensitivity to insulin and thereby reducing the requirement for over-secretion of insulin flout remaining insulin-producing beta-cells in the pancreas, i.e.
sparing these cells from subsequent "burn-out" and death. It has also been shown (Jiang ZX and Zhang ZY, Cancer Metastasis Rev. 2:263-72 (2008)) that inhibitors of P11'113 can prevent the growth of tumors and therefore be useful for the treatment of cancer.
100111 The PTPase family of enzymes can be classified into two subgroups: (1) intracellular or nontransmembrane PTPases and (2) receptor-type or transmembrane PTPases. Most known intracellular type PTPases contain a single conserved catalytic phosphatase domain consisting of 220-240 amino acid residues. The regions outside the PTPase domains are believed to play important roles in localizing the intraciellular PTPases subcellularly (Mauro, L. J. and Dixon J. E., TIES 19: 1 51 -155 (1994)). The first of the intracellular PTPases to be purified and characterized was PTP1B (Tonks et al., J.
Biol. Chem. 263: 6722-6730 (1988)). Other examples of intracellular PTPases include (1) T-cell PTPase (TCPTP) (Cool et al., Proc. Natl. Acad. Sci. USA 86: 5257-(1989)), (2) neuronal phosphatases STEP (Lombroso et al., Proc, Natl. Acad.
Sci. USA
88: 7242-7246 (1991)), (3) PTP1C/SH-PTP1/SHP-1 (Plutzky et al., Proc. Nad.
Acad.
Sci. USA 89: 1123-1127 (1992)), (4) PTP1D/Syp/SH-PPT2/SEIP-2 (Vogel et al., Science 259: 161 1-1614 (1993); Fang et al., Science 259: 1607-1611(1993)).
86: 372-378 (1994); Mol. Cell. Biol. 14: 6674-6682 (1994); The EMBO J. 12: 1937-1946 (1993); J.
Biol. Chem. 269: 30659-30667 (1994); and Biochemical Pharmacology 54: 703-711(1997)). Agents that inhibit phosphatase activity and thereby inhibit dephosphoryiation of the insulin signaling pathway, increase whole-body insulin sensitivity. This is therapeutically beneficial in treatment of insulin resistance associated with Type 11 diabetes and obesity.
RON In addition, it has been shown (Bence ICK et al., Nat Med 8:917-24 (2006)) that neuronal PTP1B in the brain regulates body weight, adiposity and leptin action.
Therefore, if a PTP1B inhibitor can cross the blood brain barrier it will not only sensitize the effect of insulin but also result in weight loss an added benefit in the treatment of type Il diabetes and in addition the treatment of obesity and its complications.
10010] There is also reported insulin resistance in Type I diabetes for which agents with PTP1B inhibitory activity would be a useful therapeutic. An insulin sensitizing agent in early type I diabetes or in a pre-diabetic statue might delay the onset of diabetes by increasing the sensitivity to insulin and thereby reducing the requirement for over-secretion of insulin flout remaining insulin-producing beta-cells in the pancreas, i.e.
sparing these cells from subsequent "burn-out" and death. It has also been shown (Jiang ZX and Zhang ZY, Cancer Metastasis Rev. 2:263-72 (2008)) that inhibitors of P11'113 can prevent the growth of tumors and therefore be useful for the treatment of cancer.
100111 The PTPase family of enzymes can be classified into two subgroups: (1) intracellular or nontransmembrane PTPases and (2) receptor-type or transmembrane PTPases. Most known intracellular type PTPases contain a single conserved catalytic phosphatase domain consisting of 220-240 amino acid residues. The regions outside the PTPase domains are believed to play important roles in localizing the intraciellular PTPases subcellularly (Mauro, L. J. and Dixon J. E., TIES 19: 1 51 -155 (1994)). The first of the intracellular PTPases to be purified and characterized was PTP1B (Tonks et al., J.
Biol. Chem. 263: 6722-6730 (1988)). Other examples of intracellular PTPases include (1) T-cell PTPase (TCPTP) (Cool et al., Proc. Natl. Acad. Sci. USA 86: 5257-(1989)), (2) neuronal phosphatases STEP (Lombroso et al., Proc, Natl. Acad.
Sci. USA
88: 7242-7246 (1991)), (3) PTP1C/SH-PTP1/SHP-1 (Plutzky et al., Proc. Nad.
Acad.
Sci. USA 89: 1123-1127 (1992)), (4) PTP1D/Syp/SH-PPT2/SEIP-2 (Vogel et al., Science 259: 161 1-1614 (1993); Fang et al., Science 259: 1607-1611(1993)).
3 100121 Receptor-type PTPases consist of (a) a putative ligand-binding extracellular domain, (b) a transmembrane segment, and (c) an intracellular catalytic region. The structure and sizes of the putative ligand-binding extmcellular domains of receptor-type PTPases are quite divergent In contrast, the intracellular catalytic regions of receptor-type PTPases are very homologous to each other and to the intracellular Fl?ases. Most receptor-type PTPases have two tandemly duplicated catalytic PTPase domains.
The first PTPase receptor subtypes identified were (1) CD45 (Ralph, S. J., EMBO J. 6:
(1987)) and (2) LAR (Streuli et aL, J. Exp. Med. 168:1523-1530 (1988)). Since then, many more receptor subtypes have been isolated and characterized, including, e.g., PTPalpba, PTPbeta, PTPdelta, PTPepsilon and PTPxi. (Krueger et al. EMBO J. 9:
3252 (1990)).
100131 Although agents have been identified for use EU PTP1B inhibitors, such as the heteroaryl- and aryl-amino acetic acids described in WO 01/19831, WO 01/19830, and WO 01/17516, these agents do not exhibit separation of the inhibitory activity between PTP1B and TCPTP. Furthermore, because of the potential immunosuppressive effects resulting from inhibiting TCPTP, selective inhibition of PIP'S over TCPTP
would make such agents more suitable for drag development as they could diminish or eliminate undesired side effects resulting from such nonselectivity.
100141 Therefore, there is a need for a drug that can safely treat diabetes by the selective inhibition of PTP1B. In addition, if neuronal PTP1B is inhibited rapid weight loss can be induced in obese Mdividuals thus also treating the effects of obesity, prevent nenrodegenemtion or Alzheimer's. A drug of this type would also be useful for the treatment of complications due to obesity, obesity in type II diabetes, high serum cholesterol, sleep apnea (especially in pickwickian syndrome), nonalcoholic steatohepatitis and surgery for obese patients. Finally, a PTP1B inhibitor could also be useful for the treatment of cancer.
SUMMARY OF THE INVENTION
100151 The present invention relates to various aminosteroids which inhibit protein phosphatase IB (PTPIB). The invention also relates to compositions which contain these aminosteroids, and methods of their use to treat diabetes in mammals, particularly humans.
The first PTPase receptor subtypes identified were (1) CD45 (Ralph, S. J., EMBO J. 6:
(1987)) and (2) LAR (Streuli et aL, J. Exp. Med. 168:1523-1530 (1988)). Since then, many more receptor subtypes have been isolated and characterized, including, e.g., PTPalpba, PTPbeta, PTPdelta, PTPepsilon and PTPxi. (Krueger et al. EMBO J. 9:
3252 (1990)).
100131 Although agents have been identified for use EU PTP1B inhibitors, such as the heteroaryl- and aryl-amino acetic acids described in WO 01/19831, WO 01/19830, and WO 01/17516, these agents do not exhibit separation of the inhibitory activity between PTP1B and TCPTP. Furthermore, because of the potential immunosuppressive effects resulting from inhibiting TCPTP, selective inhibition of PIP'S over TCPTP
would make such agents more suitable for drag development as they could diminish or eliminate undesired side effects resulting from such nonselectivity.
100141 Therefore, there is a need for a drug that can safely treat diabetes by the selective inhibition of PTP1B. In addition, if neuronal PTP1B is inhibited rapid weight loss can be induced in obese Mdividuals thus also treating the effects of obesity, prevent nenrodegenemtion or Alzheimer's. A drug of this type would also be useful for the treatment of complications due to obesity, obesity in type II diabetes, high serum cholesterol, sleep apnea (especially in pickwickian syndrome), nonalcoholic steatohepatitis and surgery for obese patients. Finally, a PTP1B inhibitor could also be useful for the treatment of cancer.
SUMMARY OF THE INVENTION
100151 The present invention relates to various aminosteroids which inhibit protein phosphatase IB (PTPIB). The invention also relates to compositions which contain these aminosteroids, and methods of their use to treat diabetes in mammals, particularly humans.
4 100161 One aspect of the invention relates to steroid compounds that are inhibitors of the enzyme PTP1B of the following formula, or a pharmaceutically acceptable salt thereof:
R4 ". Rs Rs wherein -Nli(C112)1.4-NH-126 or -OH or 0 or H or piperazine or amino piperidine;
Its-(C112)t-4-NH-R7 or CI-C3 alkyl or phenyl or H;
R7= 4C112)14-N-R11;
Re CI-Cs alkyl or benzyl or benzyl with 1-3 R9 groups Or H;
R9= -OH or -OCH3 or -C1-Cs alkyl;
R2= -OH or H;
R3= -OH or 11;
R4= -OH or H;
R3=
AI
or C1-05 alkyl ;
Rio= H or CI-Cs alkyl.
100171 Another aspect of the invention is a compound selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.
(00181 Another aspect of the invention is a pharmaceutical composition comprising a compound listed in Table 1 and a diluent or carrier.
10019) Another aspect of the invention is a method of treating or preventing diabetes in a mammal, particularly a human, comprising administering to said mammal a therapeutically effective amount of a compound of the above formula or a compound listed in Table 1.
100201 Another aspect of the invention is a method for treating a disorder in a mammal mediated by inhibition of protein tyrosine phosphatase PTP1/3 comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the above formula or a compound of Table 1.
100211 In exemplary embodiments, the disorder treated by administration of a compound of the above formula or a compound of Table 1 includes, but is not limited to, obesity in type II diabetes, high serum cholesterol, sleep apnea and nonalcoholic steatohepatitis.
BRIEF DESCRIPTION OF THE FIGURES
[0022] Figure 1 shows that MSI-1701 and 1873 treated ob/ob mice have lower fasting blood glucose levels compared to saline treated controls.
100231 Figure 2 shows a graph of the glucose tolerance test that produced the data in Figure 3.
100241 Figure 3 shows that MSI-1701 and 1873 treated ob/ob mice respond significantly faster in a glucose tolerance test than the saline treated controls.
100251 Figure 4 shows that MSI-1436 can increase the level of insulin stimulated tyrosine phosphoralation of IRP in the rat hypothalamus.
DETAILED DESCRIPTION OF THE INVENTION
[00261 The compounds listed in Table 1 are intended to include all pharmaceutically acceptable salts of the listed compounds. In addition, where the steneochetnistry at any given carbon atom is undefined, it is intended that each individual stereoisomer is encompassed as well as the racemic mixture.
100271 The aminosteroids of the invention may be administered alone or as part of a pharmaceutical composition. Pharmaceutical compositions for use in vitro or in vivo in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Examples of carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene g,lycols.
100281 In addition to carriers, the pharmaceutical compositions of the invention may also optionally inchxle stabilizers, preservatives and/or adjuvants. For examples of typical carriers, stabilizers and adjuvants known to those of skill in the art, see Remington; The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 21 ed.
(2005).
10029] Optionally, other therapies known to those of skill in the art may be combined with the administration of the aminosteroids of the invention. More than one aminosteroid may be present in a single composition.
(00301 In vivo administration of the aminosteroids of the invention can be effected in one dose, multiple doses, continuously or intermittently throughout the course of treatment.
Doses range from about 0.01 mg/kg to about 10 mg/kgõ preferably between about 0.01 mg/kg to about 1 mg/kg, and most preferably between about 0.1 mg/kg to about 1 mg/kg in single or divided daily doses. Methods of determining the most effective means and dosages of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
[0031] Pharmaceutical compositions containing the aminosteroids of the invention can be administered by any suitable route, including oral, rectal, intranasal, topical (including transdermal, aerosol, ocular, buccal and sublingual), parenteral (including subcutaneous, intramuscular, intravenous), intraperitoneal and pulmonary. It will be appreciated that the preferred route will vary with the condition and age of the recipient, and the disease being treated.
[00321 For oral administration, the aminosteroids of the invention can be formulated readily by combining them with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee coxes. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
[0033j For administration by inhalation, the arninosteroids of the present invention are conveniently delivered in the fotm of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlonatetrafluoroethane, carbon dioxide or other suitable gas.
In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0034) The aminosteroids can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage fonn, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as buffers, bacteriostats, suspending agents, stabilizing agents, thickening agents, dispersing agents or mixtures thereof.
j00351 Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
Suitable lipophilie solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or iriglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodiurn carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In a preferred embodiment, the aminostenoids of the invention are dissolved in a 5% sugar solution, such as dextrose, before being administered parentemlly.
[0036j For injection, the aminosteroids of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
100371 The aminosteroids may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional. suppository bases such as cocoa butter or other glycerides.
10038] The aminosteroids may also be combined with at least one additional therapeutic agent.
100391 Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specificrdly point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of die disclosure.
EXAMPLES
[0040] Example I -Inhibition of PTP1B by steroid analogues [00411 The steroid analogues were tested for inhibition against the commercially available full lengdi tyrosine phosphatase PTPI B. The ability of each analogue to inhibit the activity of PTP1B was measured in the presence of 10 AM of the steroid analogue.
The assay uses para-nitro-phenyl phosphate (pNPP), a non-specific substrate to assess phosphatase activity. Phosphatase activity was based on the ability of PTP1B
to catalyze the hydrolysis of pNPP to p-nitrophenol (pNP). The activity was measured using a single point spectrophometric absorbance at 405 nm (the absorbance of the chromogenic product, para-nitrophenol (pNP). The percent inhibition of tyrosine phosphatase activity by the steroid analogues was determined by the fractional response of pNP formation in the presence of inhibitor over the maximal response pNP
formation observed in the absence of inhibitor. The results of these assays are shown in Table 1, column C and show many analogues that cause greater than 50 % inhibition at 5 M
concentration.
10042) Example 2- Inhibition of TCPTP by steroid analogues 100431 The steroid analogues were also tested for their ability to inhibit the tyrosine phosphatase TCPTP as an indication of their potential toxicity by the inhibition of the immune response. The TCPIF inhibition assay was done in the same manner as the PTP1B assay except full length TCPTP was used as the enzyme and the inhibitor was at a concentration of 200 M. The results of the TCPTP inhibition assays are shown in Table 1, column D and show three compounds that inhibit TCPTP less than 50 %
even at a 20 fold greater concentration.
f00441 Example 3- Effect of steroid analogues on body weight, blood glucose levels and the oral &corm tolerance test (OGTT) in the diabetic mouse [00451 To deteimine in vivo efficacy of the steroid analogues a Db/db (Lepra) mouse model was used. Db/db mice are extensively used for screening of antidiabetic agents.
Db/db mice were treated with either saline or 5 or 10 mg/kg steroid analogue every 3 days for a total of 4 doses via ip injection. Body weight, glucose tolerance and fasting blood glucose levels were measured for each group during the study. Each group had at least an N of 4 animals. All reagents and lab animals are commercially available.
100461 Starting at study day 0, body weight measurements were taken every day for each group for up to 30 days. Percent change in body weight was calculated as the fractional response of body weight on study day X over the original body weight on study day 0.
Animals displaying a reduction in body weight suggest that the steroid analogue inhibits neuronal FTP1B as is shown for MSI-1436 in Example 4 below. Table I, coltunn G
shows % change in body weight for some 1436 analogues. MSI-1431 is seen to produce weight loss similar to 1436 but 1701 and 1873 able to inhibit PTP1B but do not produce weight loss.
10047] On study day 13, all animal groups were fasted ovemig,ht. On study day 14, 25 pi. of whole blood was collected and analyzed for the glucose level (mg/dL) using a glucose analyzer. A significant reduction of FBG levels compared to saline control is shown for MSI-1431, 1436, 1701, 1814 and 1873 in Figure 1 and Table l , column D.
[0048] Also on study day 14, an OM was performed to assess glucose tolerance.
At time 0, an oral glucose challenge (1.5 g/kg) was administered by oral gavage.
At timepoints 0, 15, 30, 60, 90, 120 min post glucose ]oad, 25 1 of whole blood was withdrawn from the tail vein of the animal and the glucose level was measured using a glucose analyzer. The glucose concentration vs time was plotted (Figure 2), Above baseline area under the curve (ABAUC) of the glucose excursion time curve was determined using trapezoidal rule analyses. A significant reduction (p<0.05) in ABAUC
compared to saline control is shown for MS1-1431, 1436, 1701, 1814 and 1873 in Figure 3 and Table 1, column F.
[0049) Example 4 Effect of MSI-1436 on the phosphorvlation of 1R-p in the rat hypothalamus [0050) Male SD rats were divided into 8 groups with 4 rats per group. All rats were fed ad libitum nonnal rodent chow and regular tap water. On Day 0, rats were dosed via intraperitoneal (i.p.) injection with 10 mg/kg MSI-1436 or 0.9% saline. Rats were fasted overnight from Day 0 to Day 1. On Day 1, anhrials were dosed i.p. with 0.9%
saline or 100 U/kg of insulin. At 15 or 30 minutes post-dose (Day 1), animals were sacrificed and the hypothalamuses were harvested, transferred to 1.5 mL eppendorf tubes, and frozen in liquid nitrogen. Samples were stored at -80 C until further analysis.
Hypothalamuses were pooled (3-4 per group) and homogenized in 2-mL Wheaton vials and Dounce homogenizers in 1 mL of tissue extraction reagent plus phosphatase and protease inhibitors. Lysates were centrifuged for 10 minutes at 4 C (14,000 rpm) and the supernatants were transferred to new 1.5 mL eppendorf tubes. Lysates (500ug) were immunoprecipitated for Insulin Receptor it overnight at 4 C. The samples were then bound to Protein A according to standard protocols for 4 hours at 4 C. Samples were then washed 4X with REPA/Empigen buffer and eluted in 4X LDS sample buffer.
After elution, the samples were boiled at 95 C for 5 min.
100511 500 ug of total protein from each sample was loaded onto a 1.5 mm 4-12%
Bis-Tris Novo( gel and run at 175V for approximately 1 hr in lx MOPS buffer. The gel was trtmsferred to nitrocellulose membrane overnight at 4 C and 10V in a Novex transfer blot apparatus and blocked the following morning in 5% BSA for 1 hr at room temperature.
Next, the membrane was incubated in anti-pTyr 4010 primary antibody diluted to 14,/ L in 1%BSA at room temperature for 2 hours. After 3 ten-minute washes in TBST, the membrane was incubated at room temperature in goat anti-mouse secondary antibody diluted 1:80,000 in 1%BSA for 1 hr. Finally, the membrane was washed 3 x 10 min in TBST, 5 x 2 min in pico pure water, and developed using SuperSignal West Pico ECL
reagent. The membrane was exposed to film for various time points.
Densitometric analysis of the bands of interest was performed using !maga The ratio of the pTyr-1R3 band to the In band was computed in Excel and the fold change in TR.
phosphorylation determined. The data indicates (Figure 4) that treatment with MSI-1436 nearly doubles the amount of phospho-Tyrosine found on insulin stimulated 1R-D in the hypothalamus.
The assumption in this case is that MSI-1436 has crossed the blood brain barrier into the hypothalamus and increased the amount of phosphor-Tyrosine on ut-p by the inhibition on PTPIB.
Table 1 Compound Structure PTP1B TCPTP % % %
Reduction in OGTT Chang Inhibition ($ inhibition Reduction Above in Body Baseline pM) (200 pM) In FBG AUC Weight . ,...
1255"----irs^ 24 IrCer 12 r.........rcisele.
go, _____________________________ , _ AN".4,1LONO.Deldr, 1303 , k 58 as , vg..."....knoyvydr 1304 ___________________________ 71 _ "4"'N'Irejl- _ 1320 44.."-'br.nrCL:r 48 0 1321 '9"-----r--irCie 28 1322 ""--"nr"..Y.C1:11.-c" 18 -Compound Structure PTP1B TCPTP %
% %
Reduction in or-r Change Inhibition (5 inhibition Reduction AbOVe in Bony Baseline PM) (200 pM) in MG AUC Weight ......"Aõ..r.n.Cle.
O.0 1352 = 38 ice ,ww1r.1016r 1370 ___________________________ es 44 '10r-,^r=C ar 1371 _________________________ , 90 0 1409 ".....--eCi 7 ....õ),............rnrCe 53 , .........42e*
'.q.
trizekrA"
v....-.
1432 22 .
-.-..........-...-1436 f"--IrCe 72 0 64 83 -8 _____________________________ >
-s--Irj:::
1437 ''.-------6 40 Compound Structure PTPIB TCPTP
Reduction In OM Change Inhibition (5 Inhibition Reduction Above in Body Baseline phil_ (200 pM) in FES AUC Weight 1520 =31 = 1521 50 Compound Structure PTPIB TCPTP %
- % %
Reduction in OGTT Change inhibition (fl inhibition Reduction Abcive in Body Baseline 1199) (200 pM) in FBG AUC Weight "A".'"Ilwr"-IrC156jr 1597 , 70 1598'9.'"..A....'nrnrCe 4 68 "P..,...."........-y....-45 9.<1 1718C7',1--Ct 19 ¨ -/
1751 .Y.s.^'1/4"#.111:21T)ti 6 _ 1755 ' 24 %.4"..
PrICI6 .y.........+ 0.4 .y.......11......- ...
11-nrCie 1783 Thri:161: 36 =
Compound Structure PTPIB TCPTP % % %
Reduction in OGTT Change Inhibition (5 Inhibition ReducUon Ab ve in Body Baseline PM) 1200 pet) In FBG AUC
Weight ---.
e o' 1804 " 10 - - ¨ - -v4......--1805 , 17 rce , 0,-,r---1810 . 30 c?...o tridsTr'''=
11".......
1811 H it 1812 n 1"
4.4.-.........11,-Ae 1814 __________________________ 56 46 60 1830 _ 15 _ vµ.......-....---sc...-.45?"
1839 n ______________________ ."Ø.,-...u......in c., _____________________________ p-1875 13fC:Cbc" 71 Q
IS
y.- ....ern ,=1:1:¶
e _ Compound Structure PTP1B TCPTP % % %
Reduction = in OGTT Change Inhibition (5 Inhibition Reduction Above in Body Baseline PhD (200 pW1) in FBG AOC
Weight _ %-c..
. ,..,..c...%
CLII
47 ' %."
yv.thlenr.lrce 1888 81 .
11---11 1111::1"
.ci;:et re"
1893I, OH 16 1894 C?"11.4:13ec.--.4, 77 .
sir:Y"
...õ,...rder 1913 38 .
0"
õ ...
.....---...--.N......õ,,....... 34 . le Compound Structure PTP113 TCPTP
Reduction in OGTT Change Inhibition (5 Inhibition Reduction = Above in Body Baseline pM) (200 pM) In FBG AUC Weight 0.3-tCe5V:FTs'jr-IC:).
2351 as 2358 = 23 Compound - Structure PTP1 iit TCPTP % % %
Reduction in 0G11* Change Inhibition (5 inhibition Reduction Above In Body Baseline pM) (200 ple) in FBG AUC .
Weight _ Ls: ¨
2363 ________________________ , 63 2365 73 , oye,^4,-k=+.46P
cr-y,~1(051:
2388 _ 37 rCIP-venrwit."-I
2371 v1 55 N5:7-*(N".1.."44).-2374 37 .
IL"A6P
2450 "-"--11--.---IrC" l 25 Compound Structure PTP113 TCPTP
% % %
Reduction in COTT Change Inhibition (5 Inhibition Reduction Above in Body Baseline pidi (200 p1129 In FSG , AUC
Weight 2451 NP----11-----vd13- r. 7 2459 17 .
"a eCiSe.
t 2485 .1...L.I.0 eel 10 .......-0--li aod5-13-' 1 2484 a I 5 V
l'filf) :II* jr tr",...-.
2490 ke 7 c 2491 Hr40 NH
..II
2492 gf*C0 2492 --L.....r 10 Compound Structure PTP1B TCPTP % % %
Reduction in ¨
TT Change inhibftion (5 Inhibition Reduction Above in Body Baseline PM) (200 All In FSG ABC Weight ito..)4' 2495 .11'L.Thr1::;61:15 7 sr4 2498 *". rdS1P. , 10 trictSiStY.-a. 15 2498 c01431T1 r 13 .
R4 ". Rs Rs wherein -Nli(C112)1.4-NH-126 or -OH or 0 or H or piperazine or amino piperidine;
Its-(C112)t-4-NH-R7 or CI-C3 alkyl or phenyl or H;
R7= 4C112)14-N-R11;
Re CI-Cs alkyl or benzyl or benzyl with 1-3 R9 groups Or H;
R9= -OH or -OCH3 or -C1-Cs alkyl;
R2= -OH or H;
R3= -OH or 11;
R4= -OH or H;
R3=
AI
or C1-05 alkyl ;
Rio= H or CI-Cs alkyl.
100171 Another aspect of the invention is a compound selected from the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.
(00181 Another aspect of the invention is a pharmaceutical composition comprising a compound listed in Table 1 and a diluent or carrier.
10019) Another aspect of the invention is a method of treating or preventing diabetes in a mammal, particularly a human, comprising administering to said mammal a therapeutically effective amount of a compound of the above formula or a compound listed in Table 1.
100201 Another aspect of the invention is a method for treating a disorder in a mammal mediated by inhibition of protein tyrosine phosphatase PTP1/3 comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of the above formula or a compound of Table 1.
100211 In exemplary embodiments, the disorder treated by administration of a compound of the above formula or a compound of Table 1 includes, but is not limited to, obesity in type II diabetes, high serum cholesterol, sleep apnea and nonalcoholic steatohepatitis.
BRIEF DESCRIPTION OF THE FIGURES
[0022] Figure 1 shows that MSI-1701 and 1873 treated ob/ob mice have lower fasting blood glucose levels compared to saline treated controls.
100231 Figure 2 shows a graph of the glucose tolerance test that produced the data in Figure 3.
100241 Figure 3 shows that MSI-1701 and 1873 treated ob/ob mice respond significantly faster in a glucose tolerance test than the saline treated controls.
100251 Figure 4 shows that MSI-1436 can increase the level of insulin stimulated tyrosine phosphoralation of IRP in the rat hypothalamus.
DETAILED DESCRIPTION OF THE INVENTION
[00261 The compounds listed in Table 1 are intended to include all pharmaceutically acceptable salts of the listed compounds. In addition, where the steneochetnistry at any given carbon atom is undefined, it is intended that each individual stereoisomer is encompassed as well as the racemic mixture.
100271 The aminosteroids of the invention may be administered alone or as part of a pharmaceutical composition. Pharmaceutical compositions for use in vitro or in vivo in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Examples of carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene g,lycols.
100281 In addition to carriers, the pharmaceutical compositions of the invention may also optionally inchxle stabilizers, preservatives and/or adjuvants. For examples of typical carriers, stabilizers and adjuvants known to those of skill in the art, see Remington; The Science and Practice of Pharmacy, Lippincott, Williams & Wilkins, 21 ed.
(2005).
10029] Optionally, other therapies known to those of skill in the art may be combined with the administration of the aminosteroids of the invention. More than one aminosteroid may be present in a single composition.
(00301 In vivo administration of the aminosteroids of the invention can be effected in one dose, multiple doses, continuously or intermittently throughout the course of treatment.
Doses range from about 0.01 mg/kg to about 10 mg/kgõ preferably between about 0.01 mg/kg to about 1 mg/kg, and most preferably between about 0.1 mg/kg to about 1 mg/kg in single or divided daily doses. Methods of determining the most effective means and dosages of administration are well known to those of skill in the art and will vary with the composition used for therapy, the purpose of the therapy, the target cell being treated and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
[0031] Pharmaceutical compositions containing the aminosteroids of the invention can be administered by any suitable route, including oral, rectal, intranasal, topical (including transdermal, aerosol, ocular, buccal and sublingual), parenteral (including subcutaneous, intramuscular, intravenous), intraperitoneal and pulmonary. It will be appreciated that the preferred route will vary with the condition and age of the recipient, and the disease being treated.
[00321 For oral administration, the aminosteroids of the invention can be formulated readily by combining them with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee coxes. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
[0033j For administration by inhalation, the arninosteroids of the present invention are conveniently delivered in the fotm of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlonatetrafluoroethane, carbon dioxide or other suitable gas.
In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0034) The aminosteroids can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage fonn, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as buffers, bacteriostats, suspending agents, stabilizing agents, thickening agents, dispersing agents or mixtures thereof.
j00351 Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions.
Suitable lipophilie solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or iriglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodiurn carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In a preferred embodiment, the aminostenoids of the invention are dissolved in a 5% sugar solution, such as dextrose, before being administered parentemlly.
[0036j For injection, the aminosteroids of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
100371 The aminosteroids may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional. suppository bases such as cocoa butter or other glycerides.
10038] The aminosteroids may also be combined with at least one additional therapeutic agent.
100391 Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the claimed methods. The following working examples therefore, specificrdly point out preferred embodiments of the present invention, and are not to be construed as limiting in any way the remainder of die disclosure.
EXAMPLES
[0040] Example I -Inhibition of PTP1B by steroid analogues [00411 The steroid analogues were tested for inhibition against the commercially available full lengdi tyrosine phosphatase PTPI B. The ability of each analogue to inhibit the activity of PTP1B was measured in the presence of 10 AM of the steroid analogue.
The assay uses para-nitro-phenyl phosphate (pNPP), a non-specific substrate to assess phosphatase activity. Phosphatase activity was based on the ability of PTP1B
to catalyze the hydrolysis of pNPP to p-nitrophenol (pNP). The activity was measured using a single point spectrophometric absorbance at 405 nm (the absorbance of the chromogenic product, para-nitrophenol (pNP). The percent inhibition of tyrosine phosphatase activity by the steroid analogues was determined by the fractional response of pNP formation in the presence of inhibitor over the maximal response pNP
formation observed in the absence of inhibitor. The results of these assays are shown in Table 1, column C and show many analogues that cause greater than 50 % inhibition at 5 M
concentration.
10042) Example 2- Inhibition of TCPTP by steroid analogues 100431 The steroid analogues were also tested for their ability to inhibit the tyrosine phosphatase TCPTP as an indication of their potential toxicity by the inhibition of the immune response. The TCPIF inhibition assay was done in the same manner as the PTP1B assay except full length TCPTP was used as the enzyme and the inhibitor was at a concentration of 200 M. The results of the TCPTP inhibition assays are shown in Table 1, column D and show three compounds that inhibit TCPTP less than 50 %
even at a 20 fold greater concentration.
f00441 Example 3- Effect of steroid analogues on body weight, blood glucose levels and the oral &corm tolerance test (OGTT) in the diabetic mouse [00451 To deteimine in vivo efficacy of the steroid analogues a Db/db (Lepra) mouse model was used. Db/db mice are extensively used for screening of antidiabetic agents.
Db/db mice were treated with either saline or 5 or 10 mg/kg steroid analogue every 3 days for a total of 4 doses via ip injection. Body weight, glucose tolerance and fasting blood glucose levels were measured for each group during the study. Each group had at least an N of 4 animals. All reagents and lab animals are commercially available.
100461 Starting at study day 0, body weight measurements were taken every day for each group for up to 30 days. Percent change in body weight was calculated as the fractional response of body weight on study day X over the original body weight on study day 0.
Animals displaying a reduction in body weight suggest that the steroid analogue inhibits neuronal FTP1B as is shown for MSI-1436 in Example 4 below. Table I, coltunn G
shows % change in body weight for some 1436 analogues. MSI-1431 is seen to produce weight loss similar to 1436 but 1701 and 1873 able to inhibit PTP1B but do not produce weight loss.
10047] On study day 13, all animal groups were fasted ovemig,ht. On study day 14, 25 pi. of whole blood was collected and analyzed for the glucose level (mg/dL) using a glucose analyzer. A significant reduction of FBG levels compared to saline control is shown for MSI-1431, 1436, 1701, 1814 and 1873 in Figure 1 and Table l , column D.
[0048] Also on study day 14, an OM was performed to assess glucose tolerance.
At time 0, an oral glucose challenge (1.5 g/kg) was administered by oral gavage.
At timepoints 0, 15, 30, 60, 90, 120 min post glucose ]oad, 25 1 of whole blood was withdrawn from the tail vein of the animal and the glucose level was measured using a glucose analyzer. The glucose concentration vs time was plotted (Figure 2), Above baseline area under the curve (ABAUC) of the glucose excursion time curve was determined using trapezoidal rule analyses. A significant reduction (p<0.05) in ABAUC
compared to saline control is shown for MS1-1431, 1436, 1701, 1814 and 1873 in Figure 3 and Table 1, column F.
[0049) Example 4 Effect of MSI-1436 on the phosphorvlation of 1R-p in the rat hypothalamus [0050) Male SD rats were divided into 8 groups with 4 rats per group. All rats were fed ad libitum nonnal rodent chow and regular tap water. On Day 0, rats were dosed via intraperitoneal (i.p.) injection with 10 mg/kg MSI-1436 or 0.9% saline. Rats were fasted overnight from Day 0 to Day 1. On Day 1, anhrials were dosed i.p. with 0.9%
saline or 100 U/kg of insulin. At 15 or 30 minutes post-dose (Day 1), animals were sacrificed and the hypothalamuses were harvested, transferred to 1.5 mL eppendorf tubes, and frozen in liquid nitrogen. Samples were stored at -80 C until further analysis.
Hypothalamuses were pooled (3-4 per group) and homogenized in 2-mL Wheaton vials and Dounce homogenizers in 1 mL of tissue extraction reagent plus phosphatase and protease inhibitors. Lysates were centrifuged for 10 minutes at 4 C (14,000 rpm) and the supernatants were transferred to new 1.5 mL eppendorf tubes. Lysates (500ug) were immunoprecipitated for Insulin Receptor it overnight at 4 C. The samples were then bound to Protein A according to standard protocols for 4 hours at 4 C. Samples were then washed 4X with REPA/Empigen buffer and eluted in 4X LDS sample buffer.
After elution, the samples were boiled at 95 C for 5 min.
100511 500 ug of total protein from each sample was loaded onto a 1.5 mm 4-12%
Bis-Tris Novo( gel and run at 175V for approximately 1 hr in lx MOPS buffer. The gel was trtmsferred to nitrocellulose membrane overnight at 4 C and 10V in a Novex transfer blot apparatus and blocked the following morning in 5% BSA for 1 hr at room temperature.
Next, the membrane was incubated in anti-pTyr 4010 primary antibody diluted to 14,/ L in 1%BSA at room temperature for 2 hours. After 3 ten-minute washes in TBST, the membrane was incubated at room temperature in goat anti-mouse secondary antibody diluted 1:80,000 in 1%BSA for 1 hr. Finally, the membrane was washed 3 x 10 min in TBST, 5 x 2 min in pico pure water, and developed using SuperSignal West Pico ECL
reagent. The membrane was exposed to film for various time points.
Densitometric analysis of the bands of interest was performed using !maga The ratio of the pTyr-1R3 band to the In band was computed in Excel and the fold change in TR.
phosphorylation determined. The data indicates (Figure 4) that treatment with MSI-1436 nearly doubles the amount of phospho-Tyrosine found on insulin stimulated 1R-D in the hypothalamus.
The assumption in this case is that MSI-1436 has crossed the blood brain barrier into the hypothalamus and increased the amount of phosphor-Tyrosine on ut-p by the inhibition on PTPIB.
Table 1 Compound Structure PTP1B TCPTP % % %
Reduction in OGTT Chang Inhibition ($ inhibition Reduction Above in Body Baseline pM) (200 pM) In FBG AUC Weight . ,...
1255"----irs^ 24 IrCer 12 r.........rcisele.
go, _____________________________ , _ AN".4,1LONO.Deldr, 1303 , k 58 as , vg..."....knoyvydr 1304 ___________________________ 71 _ "4"'N'Irejl- _ 1320 44.."-'br.nrCL:r 48 0 1321 '9"-----r--irCie 28 1322 ""--"nr"..Y.C1:11.-c" 18 -Compound Structure PTP1B TCPTP %
% %
Reduction in or-r Change Inhibition (5 inhibition Reduction AbOVe in Bony Baseline PM) (200 pM) in MG AUC Weight ......"Aõ..r.n.Cle.
O.0 1352 = 38 ice ,ww1r.1016r 1370 ___________________________ es 44 '10r-,^r=C ar 1371 _________________________ , 90 0 1409 ".....--eCi 7 ....õ),............rnrCe 53 , .........42e*
'.q.
trizekrA"
v....-.
1432 22 .
-.-..........-...-1436 f"--IrCe 72 0 64 83 -8 _____________________________ >
-s--Irj:::
1437 ''.-------6 40 Compound Structure PTPIB TCPTP
Reduction In OM Change Inhibition (5 Inhibition Reduction Above in Body Baseline phil_ (200 pM) in FES AUC Weight 1520 =31 = 1521 50 Compound Structure PTPIB TCPTP %
- % %
Reduction in OGTT Change inhibition (fl inhibition Reduction Abcive in Body Baseline 1199) (200 pM) in FBG AUC Weight "A".'"Ilwr"-IrC156jr 1597 , 70 1598'9.'"..A....'nrnrCe 4 68 "P..,...."........-y....-45 9.<1 1718C7',1--Ct 19 ¨ -/
1751 .Y.s.^'1/4"#.111:21T)ti 6 _ 1755 ' 24 %.4"..
PrICI6 .y.........+ 0.4 .y.......11......- ...
11-nrCie 1783 Thri:161: 36 =
Compound Structure PTPIB TCPTP % % %
Reduction in OGTT Change Inhibition (5 Inhibition ReducUon Ab ve in Body Baseline PM) 1200 pet) In FBG AUC
Weight ---.
e o' 1804 " 10 - - ¨ - -v4......--1805 , 17 rce , 0,-,r---1810 . 30 c?...o tridsTr'''=
11".......
1811 H it 1812 n 1"
4.4.-.........11,-Ae 1814 __________________________ 56 46 60 1830 _ 15 _ vµ.......-....---sc...-.45?"
1839 n ______________________ ."Ø.,-...u......in c., _____________________________ p-1875 13fC:Cbc" 71 Q
IS
y.- ....ern ,=1:1:¶
e _ Compound Structure PTP1B TCPTP % % %
Reduction = in OGTT Change Inhibition (5 Inhibition Reduction Above in Body Baseline PhD (200 pW1) in FBG AOC
Weight _ %-c..
. ,..,..c...%
CLII
47 ' %."
yv.thlenr.lrce 1888 81 .
11---11 1111::1"
.ci;:et re"
1893I, OH 16 1894 C?"11.4:13ec.--.4, 77 .
sir:Y"
...õ,...rder 1913 38 .
0"
õ ...
.....---...--.N......õ,,....... 34 . le Compound Structure PTP113 TCPTP
Reduction in OGTT Change Inhibition (5 Inhibition Reduction = Above in Body Baseline pM) (200 pM) In FBG AUC Weight 0.3-tCe5V:FTs'jr-IC:).
2351 as 2358 = 23 Compound - Structure PTP1 iit TCPTP % % %
Reduction in 0G11* Change Inhibition (5 inhibition Reduction Above In Body Baseline pM) (200 ple) in FBG AUC .
Weight _ Ls: ¨
2363 ________________________ , 63 2365 73 , oye,^4,-k=+.46P
cr-y,~1(051:
2388 _ 37 rCIP-venrwit."-I
2371 v1 55 N5:7-*(N".1.."44).-2374 37 .
IL"A6P
2450 "-"--11--.---IrC" l 25 Compound Structure PTP113 TCPTP
% % %
Reduction in COTT Change Inhibition (5 Inhibition Reduction Above in Body Baseline pidi (200 p1129 In FSG , AUC
Weight 2451 NP----11-----vd13- r. 7 2459 17 .
"a eCiSe.
t 2485 .1...L.I.0 eel 10 .......-0--li aod5-13-' 1 2484 a I 5 V
l'filf) :II* jr tr",...-.
2490 ke 7 c 2491 Hr40 NH
..II
2492 gf*C0 2492 --L.....r 10 Compound Structure PTP1B TCPTP % % %
Reduction in ¨
TT Change inhibftion (5 Inhibition Reduction Above in Body Baseline PM) (200 All In FSG ABC Weight ito..)4' 2495 .11'L.Thr1::;61:15 7 sr4 2498 *". rdS1P. , 10 trictSiStY.-a. 15 2498 c01431T1 r 13 .
Claims (10)
1. A compound or pharmaceutically acceptable salt thereof selected from the group consisting of
2. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
3. A method for treating diabetes in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula or a pharmaceutically acceptable salt thereof, wherein:
R1= -NH(CH2)14-NH-R6 or -OH or =O or H or piperazine or amino piperidine;
R6= -(CH2)1-4-NH-R7 or C1-C5 alkyl or phenyl or H;
R7= -(CH2)1-4-N-R8;
R8= C1-C5 alkyl or benzyl or benzyl with 1-3 R9 groups or H;
R9= -OH or -OCH3 or -C1-C5 alkyl;
R2= -OH or H;
R3= -OH or H;
R4= -OH or H;
R5=
or C1-C5 alkyl;
R10= H or C1-C5 alkyl.
R1= -NH(CH2)14-NH-R6 or -OH or =O or H or piperazine or amino piperidine;
R6= -(CH2)1-4-NH-R7 or C1-C5 alkyl or phenyl or H;
R7= -(CH2)1-4-N-R8;
R8= C1-C5 alkyl or benzyl or benzyl with 1-3 R9 groups or H;
R9= -OH or -OCH3 or -C1-C5 alkyl;
R2= -OH or H;
R3= -OH or H;
R4= -OH or H;
R5=
or C1-C5 alkyl;
R10= H or C1-C5 alkyl.
4. A method for treating diabetes in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
5. The method according to claim 3 or claim 4, wherein the diabetes is type I diabetes.
6. The method according to claim 3 or claim 4, wherein the diabetes is type II diabetes.
7. A method of treating a disorder in a mammal mediated by inhibition of protein tyrosine phosphatase PTP1B comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula or a pharmaceutically acceptable salt thereof, wherein:
R1= -NH(CH2)1-4-NH-R6 or -OH or =O or H or piperazine or amino piperidine;
R6= -(CH2)1-4-NH-R7 or C1-C5 alkyl or phenyl or H;
R7= -(CH2)1-4-N-R8;
R8= C1-C5 alkyl or benzyl or benzyl with 1-3 R9 groups or H;
R9= -OH or -OCH3 or -C1-C5 alkyl;
R2= -OH or H;
R3= -OH or H;
R4= -OH or H;
R5=
, or C1-C5 alkyl;
R10= H or C1-C5 alkyl.
R1= -NH(CH2)1-4-NH-R6 or -OH or =O or H or piperazine or amino piperidine;
R6= -(CH2)1-4-NH-R7 or C1-C5 alkyl or phenyl or H;
R7= -(CH2)1-4-N-R8;
R8= C1-C5 alkyl or benzyl or benzyl with 1-3 R9 groups or H;
R9= -OH or -OCH3 or -C1-C5 alkyl;
R2= -OH or H;
R3= -OH or H;
R4= -OH or H;
R5=
, or C1-C5 alkyl;
R10= H or C1-C5 alkyl.
8. A method of treating a disorder in a mammal mediated by inhibition of protein tyrosine phosphatase PTP1B comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.
9. The method of claim 7 or claim 8, wherein the disorder is selected from obesity, high serum cholesterol, sleep apnea and nonalcoholic steatohepatitis.
10. The method of claim 9, wherein the obesity is associated with type II
diabetes.
diabetes.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US97046707P | 2007-09-06 | 2007-09-06 | |
| US60/970,467 | 2007-09-06 | ||
| CA2922021A CA2922021C (en) | 2007-09-06 | 2008-09-08 | A method for treating diabetes |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2922021A Division CA2922021C (en) | 2007-09-06 | 2008-09-08 | A method for treating diabetes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2985271A1 true CA2985271A1 (en) | 2009-03-12 |
Family
ID=40429620
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2985271A Abandoned CA2985271A1 (en) | 2007-09-06 | 2008-09-08 | A method for treating diabetes |
| CA2697744A Expired - Fee Related CA2697744C (en) | 2007-09-06 | 2008-09-08 | A method for treating diabetes |
| CA2922021A Expired - Fee Related CA2922021C (en) | 2007-09-06 | 2008-09-08 | A method for treating diabetes |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2697744A Expired - Fee Related CA2697744C (en) | 2007-09-06 | 2008-09-08 | A method for treating diabetes |
| CA2922021A Expired - Fee Related CA2922021C (en) | 2007-09-06 | 2008-09-08 | A method for treating diabetes |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US9365608B2 (en) |
| EP (2) | EP2188299B1 (en) |
| JP (1) | JP2010538072A (en) |
| CA (3) | CA2985271A1 (en) |
| TW (1) | TW200927755A (en) |
| WO (1) | WO2009032321A2 (en) |
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-
2008
- 2008-09-08 CA CA2985271A patent/CA2985271A1/en not_active Abandoned
- 2008-09-08 TW TW097134424A patent/TW200927755A/en unknown
- 2008-09-08 CA CA2697744A patent/CA2697744C/en not_active Expired - Fee Related
- 2008-09-08 JP JP2010524047A patent/JP2010538072A/en active Pending
- 2008-09-08 EP EP08829680.1A patent/EP2188299B1/en not_active Not-in-force
- 2008-09-08 EP EP17198056.8A patent/EP3293195A1/en not_active Withdrawn
- 2008-09-08 WO PCT/US2008/010455 patent/WO2009032321A2/en active Application Filing
- 2008-09-08 US US12/676,701 patent/US9365608B2/en not_active Expired - Fee Related
- 2008-09-08 CA CA2922021A patent/CA2922021C/en not_active Expired - Fee Related
-
2016
- 2016-06-09 US US15/178,335 patent/US20160362444A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20100324004A1 (en) | 2010-12-23 |
| EP2188299B1 (en) | 2017-10-25 |
| CA2922021A1 (en) | 2009-03-12 |
| CA2922021C (en) | 2018-01-09 |
| JP2010538072A (en) | 2010-12-09 |
| WO2009032321A2 (en) | 2009-03-12 |
| WO2009032321A3 (en) | 2009-05-22 |
| EP3293195A1 (en) | 2018-03-14 |
| TW200927755A (en) | 2009-07-01 |
| CA2697744C (en) | 2016-06-14 |
| EP2188299A4 (en) | 2012-12-12 |
| US9365608B2 (en) | 2016-06-14 |
| CA2697744A1 (en) | 2009-03-12 |
| US20160362444A1 (en) | 2016-12-15 |
| EP2188299A2 (en) | 2010-05-26 |
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